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Chemoprevention clinical trials
Mutation Research, 267 (1992) 291-295
291
Q 1992 Elsevier Science Publishers B.V. All rights reserved 0027-5107/92/$05.00
MUT
00302
Chemoprevention
clinical trials
Gary J. Kelloff, Charles W. Boone, Winfred F. Malone and Vernon E. Steele Chcmoprer:ention Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (U.S.A.) (Received 1 August 1991) (Accepted 8 October 1991)
Keywords: Anticarcinogenesis;
Chemoprevention;
Cancer prevention; Retinoids; p-carotene;
Calcium compounds
Summary As part of a program to develop drugs which will delay or prevent cancer in humans, the Chemoprevention Branch, National Cancer Institute, National Institutes of Health, is sponsoring 12 Phase I and 22 Phase II and III clinical trials. Three agent classes are significantly advanced in the trials. These are the retinoids, including 13~cis-retinoic acid, retinol, and 4-hydroxyphenylretinamide (nine studies), p-carotene (seven studies), and calcium compounds (three studies). In addition, six promising new compounds are in Phase I or Phase II triaIs. These are: piroxicam, ibuprofen, oltipraz (a dithiolthione), difluoromethylornithine, glycyrrhetinic acid, and N-acetylcysteine. Key concepts related to the development of cancer chemopreventive agents are (1) the need for long-term administration, (2) the need for oral route of administration, (3) the matching of toxic side effects to degree of cancer risk.
The last stages in the development of chemopreventive drugs are the clinical trials, which are conducted in three phases of increasing scale. Phase I trials are concerned primarily with safety and toxicity of the proposed chemopreventive agent. Pharmacokinetic properties are assessed at this stage, including blood level kinetics after single and multiple doses. The characteristics of absorption, distribution, metabolism, and excretion are also determined. Phase II trials are small scale efficacy studies, and sometimes have as an endpoint the modulation of an intermediate marker, such as moderate to severe dysplasia,
Correspondence: Branch, Health,
National
Dr.
Gary
Cancer
J.
Kelloff,
Institute,
Bethesda, MD 20892 (U.S.A.).
Chemoprevention
National
Institutes
of
rather than the reduction of cancer incidence. Phase III trials are large efficacy studies, with the usual endpoint bcinq rcducr:ion of cairccr incidence. It is informative to note the differences between a Phase I chemoprevention trial and a Phase I cancer treatment trial. In a cancer treatment trial, the maximum tolerated dose is required; this dose is not necessary or desirable in a chemoprevention trial because little or no toxicity can be tolerated in the latter. Once a safe dose is selected by completion of the Phase I trial, inferences can be drawn about the likelihood that it is an effective dose. However, the true efficacy (and longer term safety) of the selected dose may only be known after the conduct of the Phase II and Phase III trials. Along with the selection of dose, there are other differences between a standard treatment
2~
trial and a trial for chemoprevcntive agents. For example, treatment trials are designed to treat already existing diseases; cancer prevention trials are designed to effect changes at the subclinical or perhaps even the molecular level. Thus, the populations are quite different. A patient with a disease is considered ill, whereas an individual at risk is most likely considered healthy. These important differences must guide the concepts and principles that relate to the design, execution, and evaluation of all chemoprevention trials. The program of the NCI Branch
Chemoprevention
The Chemoprevention Program of the Division of Cancer Prevention and Control at the National Cancer Institute, National Institutes of Health, has developed a program to identify and develop for human use drugs which will prevent or suppress the development of cancer. At the present time the Chemoprevention Branch is sponsoring 12 Phase I and 22 Phase II and III trials. The compounds being tested, and the type of clinical trial, are summarized in Table 1. As thc table shows, three agent classes are significantly advanced in clinical trials. These may be called the first generation of candidate chemopreventive agents. They are the retinoids (nine studies), B-carotene (seven studies), and calcium compounds (three studies). In addition, a second generation of six promising new compounds are in Phase 1 trials. These are piroxicam, ibuprofen, oltipraz (a dithiolthione), difluoromethylornithine, glycyrrhetinic acid, and N-acetylcysteine. Published results of previous chemoprevention clinical trials exist principally for the retinoids tHong et al., 1986, 1990; Lippman et al., 1989; Stich et al., 1989) and /3~carotenc (Greenberg et al., 1990; Garewal et al., 1990; Stich et al., 1989). A study is available on the effect of vitamins C and E in the preve, tion of recurrence of colorectal polyps (McEown-Eyssen et al., 1988), and another on the improvement of bronchial squamous metaplasia in smokcrs treated with folate and vitamin B12 (Heimburger et al., 1988). Table 2 lists the clinical trials classified on the basis of organ site, as follows. SKIN; prevention of additional basal cell carcinomas (BCC): two
TABLE 1 CHECKLIST OF ONGOING PHASE 1, II, AND ili CLINICAL STUDIES BEING SPONSORED BY THE CHEMOPREVENTION BRANCH The number in parentheses after a checkmark indicates the total number of studies being conducted for the test chemopreventive agent indicated. A checkmark alone indicates a single study Phase I
Phase II
Phase II!
((2) ((2)
( ( ((2) (
Retinoids
4-HPR 13-cis-Retinoic acid Retinol all-trans-Retinoic acid
( (
/3-Carotene Calcium Piroxicam DFMO
(
Oltipraz Glycyrrhetinic acid N-AcetyI-L-Cysteine Ibuprofen Folic acid Vitamins C and E
((2) ( ( (
( (/-(3)
((5) ((3) ( (
(t2)
vr (
studies, and prevention of additional actinic keratoses: one study. The recent study by Greenberg (1990) led to the conclusion that in persons with a previous nonmelanoma skin cancer, treatment with /3-carotene does not reduce the occurrence of new skin cancers over a 5-year period of treatment and observation. ORAL CAVITY; prevention of oral leukoplakia: one study. In a previous study on the treatment of oral leukoplakia with 13-cis-retinoic acid, Hong (1986) reported the reversal of dysplasia in 54% (13 patients) of the drug group and in 10% (2 patients) of the placebo group. BREAST; prevention of second primary of the breast: two studies. LUNG; prevention of lung cancer: three studies, and prevention of bronchial dysplasia: one study, all in chronic tobacco smokers. COLON; prevention of additional colon adenomas: nine studies. U T E R I N E CERVIX; prevention of cervical dysplasia: two studies.
293 TABLE 2 CLINICAL TRIALS SPONSORED BY THE CHEMOPREVENTION BRANCH LISTED BY ORGAN SYSTEM Study title
Population
Agent/dosage and schedule
Principal investigator
Duration, years
Skin Chemoprevention of skin and oral cancer
Previous BCC of skin
Retinol 25 000 IU/day vs. 13-c/s-retinoic acid 0.15 mg/kg g-Carotene 50 mg/day
David S. Alberts, M.D. University of Arizona
13
719
Robert E. Greenberg, M.D. Dartmouth College
10
1805
Previous actinic keratosis
Retinoi 25 000 I U / D a y
Thomas E. Moon, Ph.D. University of Arizona
9
2800
Oral leukoplakia
13-cis-Retinoic acid 1.5 mg/kg for 3 mos.; then 0.5 mg/kg daily for 9 mos. or g-carotene 30 rag/day for 9 mos.
Waun K. Hong, M.D. University of Texas
4
65
Post-op stage I breast cancer
Tamoxifen 20 mg/day
William McWhorter, M.D., M.P.H. University of Utah
5
120
Post-op stage I breast cancer
4-HPR (fenretinide) 200 rag/day
Umberto Veronesi, M.D. Nazionale Tumori Milan, Italy
Smoking nurses
g-Carotene 50 mg QOD + vitamin E 600 mg QOD 13-c/s-Retinoic acid 1.0 mg/kg daily
Julie E. Buring, D.Ss. Brigham & Women's Hospital, Boston
5
19000
Waun K. Hong, M.D. University of Texas
4
150
Retinol 25000 IU QOD g-Carotene 30 rag/day + retinol 25 000 IU/day
Jerry W. McLarty, Ph.D. University of Texas Gilbert S. Omenn, M.D. University of Washington
Chemoprevention trial of g-carotene in skin cancer Chemoprevention of skin cancer by vitamin A:
Oral cacity Chemoprevention of human premalignant oral lesions
Breast Effect of tamoxifen on proliferative breast disease Breast cancer prevention with synthetic retinoid (4-HPR)
Lung Trial of g.carotene and lung cancer Chemoprevention of human bronchial dysplasia Retinol and lung cancer Carotenoid and retinoid efficacy trial (CARET) 6 study sites: Seattle, Portland, Irvine, San Francisco, Baltimore, New Haven
Previous BCC of skin
Chronic smokers, bronchial dysplr sia Chronic smokers Chronic smokers (4000 asbestos exposed)
Study population
5000
758 14O0O smokers
(4,000 asbestos exposed)
294 TABLE 2 (continued) Study title
Colon Colon cancer prevention program project (Piroxicam) Colon cancer prevention program project (Fiber) Colon cancer prevention program project (DFMO) Calcium in the prevention of neoplastic polyps Sulindac chemoprevention in adenomatous polyposis coil Nutritional prevention of polyps in the large bowel Chemoprevention using DFMO to modulate ODC Effect cf
/3.carotene on colonic cell proliferation Calcium and colorectal epithelial cell proliferation
Cer~'ix ~-Carotene clinical trial monitoring cervical dysplasia Phase II intervention trial for cervical dysplasia
Population
Agent/dosage and schedule
Principal investigator
Duration, years
Study population
Prior colon adenoma
Piroxicam 7.5 mg/day
David S. AIberts, M.D. University of Arizona
9
100
Prior colon adenoma
Wheat Bran 13.5 g/day
David S. AIberts, M.D. University of Arizona
9
100
Prior colon adenoma
David S. AIberts, M.D. University of Arizona
9
25
Prior colon adenoma
DFMO 3, !.5, 0.75, 0.50, 0.25 Calcium carbonate 3 g/day
John A. Barton, M.D. Dartmouth College
5
637
Familial adenomatous polyposis
Sulindac 150 rag, 2 day for 9 months
Francis M. Giardiello, M.D. Johns Hopkins University
2
New Study
Prior colon adenoma
Vitamin E Vitamin C
Robert E. Greenberg, M.D. Dartmouth College
9
865
Prior colon adenoma
DFMO
Gordon D. Luk, M.D. Wayne State University
3
New Study
Prior colon
~-Carotene
Sohrab Mobarhan, M.D.
4
100 Planned
cancer
30 rag/day
Loyola Universityof Chicago
Prior colon adenoma
Calcium carbonate 3 |o 5 g/day
John D. Potter, M.D., Ph,D. University of Minnesota
3
New Study
Cervical dysplasia
~-Carotene 30 rag/day
Seymour L. Romney, M.D. Albert Einstein College of Medicine
4
New Study
Cervical dysplasia
[3.trans-Retinoic acid 0.372% tropical cervical cap
Earl A. Surwit, M.D. University of Arizona
7
301
Key concepts related to the development of cancer chemopreventlve agents
Long term of admin;,stration. Chemopreventive agents, which generally act either as antimutagens, as antiproliferafives, or as both, will have
~o be given to normal individuals over a period of years or even a lifetime.
Oral route of administration. Generally, a chemopreventive agent will be given by the oral route because it will be administered to normal individuals over a long period of time. Basic
295
investigators should therefore be aware that for a candidate chemopreventive agent to have potential, it will have to survive the digestive processes of the gastrointestinal tract.
Matching of toxic side effects to degree of cancer r/sk. In the event that a cancer chemopreventive agent is efficacious but is associated with significant side effects, the target population to consider will have to be one with higher cancer risk. For example, the severe oral and nasal irritation and drying associated with 13-c/s-retinoic acid, while objectionable to normal individuals, would be tolerated by persons who have had a carcinoma of the aerodigestive tract removed and carry a 10% chance of developing a second primary cancer of the esophagus, larynx, oral cavity, or lung. Conclusions
Twelve Phase I and 22 Phase II and III clinical trials sponsored by the Chemoprevention Branch are under way. The Phase II and III trials are testing the first generation of candidate chemopreventive agents, which are the retinoids, /3carotene, and calcium compounds. A second generation of six promising new compounds are in Phase I clinical trials. A problem of increasing concern is the time span of many years required to carry out a full clinical evaluation of a candidate chemopreventive agent. One important solution will be the development and validation of intermediate biomarkers of cancer, i.e., precancerous biological changes in target epithelia that are strongly associated with cancer risk and that can be modulated with a chemopreventive agent. Such intermediate markers could significantly shorten the clinical efficacy evaluation of promising agents in Phase II trials. Examples of such epithelial markers are abnormal histology (dysplasia), prevention or reversal of nuclear aberrations (micronuclei), ornithine decarboxylase a n d / o r prostaglandin
synthase inhibition, DNA ploidy alterations, and changes in epithelial proliferation rate (tritiated thymidine labeling, various antigens associated with proliferation, S-phase fraction by flow cytometry). The clinical studies presented indicate that it may not be unduly optimistic that clinical chemoprevention research will begin to yield practical applications for the reduction of cancer incidence by the end of the decade. References Garewal, H.S., F.L. Meyskens Jr., D. Killen, D. Reeves, T.A. Kiersch, H. Elletson, A. Strosbcrg, D. King and IC Steinbronn (1990) Response of oral leukoplakia to beta carotene, J. Cl'~l~.Oncol., 8, 1715-1720. Greenberg, E.R., J.A. Baron, T.A. Stukel, M.M. Stevens, J.S. Mandel, S.K. Spencer, P.M. Elias, N.Lowe, D.W. Nierenberg, G. Bayrd, J.C. Vance, D.H. Freeman, W.E. Clendenning and T. Kwan (1990) A clinical trial of beta carotene to prevent basal-cell and squamous-celi cancers of the skin, N. Engl. J. Med., 323, 825-827. Heimburger, D.C., C.B. Alexander, R. Birch, C.WE. Butterworth, W.C. Bailey and C.L. Krumdieck (1988) Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin BI2, J. Am. Med. Assoc., 259, 1525-1530. Hong, W.K., J. Endicott, L.M. ltri, W. Doos. J.G. Batsakis, R. Bell, S. Fofonoff, R. Byers, E.N. Atkinson, D. Vaughan, B.B. Toth, A. Kramer, I.W. Dimery, P. Skipper and S. Strong (1986) 13-ds-Retincic acid in the treatment of oral leukoplakia, N. Engl. J. Med., 315, 1501-1505. Hong, K.H., S.M. Lippman, L.M.ltri, D.D Karp, J.S. Lee, R.M. B~,rs, S.P. Schantz, A.M. Kramer, R. Lotan, L.J. Peters, I.vV. Dimery, B.W. Brown and H. Goepfert (1990) Prevention of second primary tumors with isotretmoin in squamous-cell carcinoma of the head and neck, N. Engl. J. Med., 323, 795-801. Lippman, S.M., H.S. Garewal and F.L. Meyskens Jr. (1989) Retinoids as potential chemopreventive agents in squamous cell carcinoma of the head and neck, Prey. Med., 18, 740-748. McKeown-Eyssen, G., C. Holloway, V. Jazmaji, E. Bright.See, P. Dion and W.R. Bruce (1988) A randomized trial c,f vitamins C and E in the prevention and recurrence of colorectal polyps, Cancer Res., 48, 4701-4705. Stich, H.F., K.D. Brunnemann, B. Mathew, R. Sankar~t / / J" narayanan and I,v~.K. Nair (1989) Chemopreventive trials with vitamin A and beta-car0tene: some unresolved issues, Prey. Med., 18, 732-739.
291
Q 1992 Elsevier Science Publishers B.V. All rights reserved 0027-5107/92/$05.00
MUT
00302
Chemoprevention
clinical trials
Gary J. Kelloff, Charles W. Boone, Winfred F. Malone and Vernon E. Steele Chcmoprer:ention Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (U.S.A.) (Received 1 August 1991) (Accepted 8 October 1991)
Keywords: Anticarcinogenesis;
Chemoprevention;
Cancer prevention; Retinoids; p-carotene;
Calcium compounds
Summary As part of a program to develop drugs which will delay or prevent cancer in humans, the Chemoprevention Branch, National Cancer Institute, National Institutes of Health, is sponsoring 12 Phase I and 22 Phase II and III clinical trials. Three agent classes are significantly advanced in the trials. These are the retinoids, including 13~cis-retinoic acid, retinol, and 4-hydroxyphenylretinamide (nine studies), p-carotene (seven studies), and calcium compounds (three studies). In addition, six promising new compounds are in Phase I or Phase II triaIs. These are: piroxicam, ibuprofen, oltipraz (a dithiolthione), difluoromethylornithine, glycyrrhetinic acid, and N-acetylcysteine. Key concepts related to the development of cancer chemopreventive agents are (1) the need for long-term administration, (2) the need for oral route of administration, (3) the matching of toxic side effects to degree of cancer risk.
The last stages in the development of chemopreventive drugs are the clinical trials, which are conducted in three phases of increasing scale. Phase I trials are concerned primarily with safety and toxicity of the proposed chemopreventive agent. Pharmacokinetic properties are assessed at this stage, including blood level kinetics after single and multiple doses. The characteristics of absorption, distribution, metabolism, and excretion are also determined. Phase II trials are small scale efficacy studies, and sometimes have as an endpoint the modulation of an intermediate marker, such as moderate to severe dysplasia,
Correspondence: Branch, Health,
National
Dr.
Gary
Cancer
J.
Kelloff,
Institute,
Bethesda, MD 20892 (U.S.A.).
Chemoprevention
National
Institutes
of
rather than the reduction of cancer incidence. Phase III trials are large efficacy studies, with the usual endpoint bcinq rcducr:ion of cairccr incidence. It is informative to note the differences between a Phase I chemoprevention trial and a Phase I cancer treatment trial. In a cancer treatment trial, the maximum tolerated dose is required; this dose is not necessary or desirable in a chemoprevention trial because little or no toxicity can be tolerated in the latter. Once a safe dose is selected by completion of the Phase I trial, inferences can be drawn about the likelihood that it is an effective dose. However, the true efficacy (and longer term safety) of the selected dose may only be known after the conduct of the Phase II and Phase III trials. Along with the selection of dose, there are other differences between a standard treatment
2~
trial and a trial for chemoprevcntive agents. For example, treatment trials are designed to treat already existing diseases; cancer prevention trials are designed to effect changes at the subclinical or perhaps even the molecular level. Thus, the populations are quite different. A patient with a disease is considered ill, whereas an individual at risk is most likely considered healthy. These important differences must guide the concepts and principles that relate to the design, execution, and evaluation of all chemoprevention trials. The program of the NCI Branch
Chemoprevention
The Chemoprevention Program of the Division of Cancer Prevention and Control at the National Cancer Institute, National Institutes of Health, has developed a program to identify and develop for human use drugs which will prevent or suppress the development of cancer. At the present time the Chemoprevention Branch is sponsoring 12 Phase I and 22 Phase II and III trials. The compounds being tested, and the type of clinical trial, are summarized in Table 1. As thc table shows, three agent classes are significantly advanced in clinical trials. These may be called the first generation of candidate chemopreventive agents. They are the retinoids (nine studies), B-carotene (seven studies), and calcium compounds (three studies). In addition, a second generation of six promising new compounds are in Phase 1 trials. These are piroxicam, ibuprofen, oltipraz (a dithiolthione), difluoromethylornithine, glycyrrhetinic acid, and N-acetylcysteine. Published results of previous chemoprevention clinical trials exist principally for the retinoids tHong et al., 1986, 1990; Lippman et al., 1989; Stich et al., 1989) and /3~carotenc (Greenberg et al., 1990; Garewal et al., 1990; Stich et al., 1989). A study is available on the effect of vitamins C and E in the preve, tion of recurrence of colorectal polyps (McEown-Eyssen et al., 1988), and another on the improvement of bronchial squamous metaplasia in smokcrs treated with folate and vitamin B12 (Heimburger et al., 1988). Table 2 lists the clinical trials classified on the basis of organ site, as follows. SKIN; prevention of additional basal cell carcinomas (BCC): two
TABLE 1 CHECKLIST OF ONGOING PHASE 1, II, AND ili CLINICAL STUDIES BEING SPONSORED BY THE CHEMOPREVENTION BRANCH The number in parentheses after a checkmark indicates the total number of studies being conducted for the test chemopreventive agent indicated. A checkmark alone indicates a single study Phase I
Phase II
Phase II!
((2) ((2)
( ( ((2) (
Retinoids
4-HPR 13-cis-Retinoic acid Retinol all-trans-Retinoic acid
( (
/3-Carotene Calcium Piroxicam DFMO
(
Oltipraz Glycyrrhetinic acid N-AcetyI-L-Cysteine Ibuprofen Folic acid Vitamins C and E
((2) ( ( (
( (/-(3)
((5) ((3) ( (
(t2)
vr (
studies, and prevention of additional actinic keratoses: one study. The recent study by Greenberg (1990) led to the conclusion that in persons with a previous nonmelanoma skin cancer, treatment with /3-carotene does not reduce the occurrence of new skin cancers over a 5-year period of treatment and observation. ORAL CAVITY; prevention of oral leukoplakia: one study. In a previous study on the treatment of oral leukoplakia with 13-cis-retinoic acid, Hong (1986) reported the reversal of dysplasia in 54% (13 patients) of the drug group and in 10% (2 patients) of the placebo group. BREAST; prevention of second primary of the breast: two studies. LUNG; prevention of lung cancer: three studies, and prevention of bronchial dysplasia: one study, all in chronic tobacco smokers. COLON; prevention of additional colon adenomas: nine studies. U T E R I N E CERVIX; prevention of cervical dysplasia: two studies.
293 TABLE 2 CLINICAL TRIALS SPONSORED BY THE CHEMOPREVENTION BRANCH LISTED BY ORGAN SYSTEM Study title
Population
Agent/dosage and schedule
Principal investigator
Duration, years
Skin Chemoprevention of skin and oral cancer
Previous BCC of skin
Retinol 25 000 IU/day vs. 13-c/s-retinoic acid 0.15 mg/kg g-Carotene 50 mg/day
David S. Alberts, M.D. University of Arizona
13
719
Robert E. Greenberg, M.D. Dartmouth College
10
1805
Previous actinic keratosis
Retinoi 25 000 I U / D a y
Thomas E. Moon, Ph.D. University of Arizona
9
2800
Oral leukoplakia
13-cis-Retinoic acid 1.5 mg/kg for 3 mos.; then 0.5 mg/kg daily for 9 mos. or g-carotene 30 rag/day for 9 mos.
Waun K. Hong, M.D. University of Texas
4
65
Post-op stage I breast cancer
Tamoxifen 20 mg/day
William McWhorter, M.D., M.P.H. University of Utah
5
120
Post-op stage I breast cancer
4-HPR (fenretinide) 200 rag/day
Umberto Veronesi, M.D. Nazionale Tumori Milan, Italy
Smoking nurses
g-Carotene 50 mg QOD + vitamin E 600 mg QOD 13-c/s-Retinoic acid 1.0 mg/kg daily
Julie E. Buring, D.Ss. Brigham & Women's Hospital, Boston
5
19000
Waun K. Hong, M.D. University of Texas
4
150
Retinol 25000 IU QOD g-Carotene 30 rag/day + retinol 25 000 IU/day
Jerry W. McLarty, Ph.D. University of Texas Gilbert S. Omenn, M.D. University of Washington
Chemoprevention trial of g-carotene in skin cancer Chemoprevention of skin cancer by vitamin A:
Oral cacity Chemoprevention of human premalignant oral lesions
Breast Effect of tamoxifen on proliferative breast disease Breast cancer prevention with synthetic retinoid (4-HPR)
Lung Trial of g.carotene and lung cancer Chemoprevention of human bronchial dysplasia Retinol and lung cancer Carotenoid and retinoid efficacy trial (CARET) 6 study sites: Seattle, Portland, Irvine, San Francisco, Baltimore, New Haven
Previous BCC of skin
Chronic smokers, bronchial dysplr sia Chronic smokers Chronic smokers (4000 asbestos exposed)
Study population
5000
758 14O0O smokers
(4,000 asbestos exposed)
294 TABLE 2 (continued) Study title
Colon Colon cancer prevention program project (Piroxicam) Colon cancer prevention program project (Fiber) Colon cancer prevention program project (DFMO) Calcium in the prevention of neoplastic polyps Sulindac chemoprevention in adenomatous polyposis coil Nutritional prevention of polyps in the large bowel Chemoprevention using DFMO to modulate ODC Effect cf
/3.carotene on colonic cell proliferation Calcium and colorectal epithelial cell proliferation
Cer~'ix ~-Carotene clinical trial monitoring cervical dysplasia Phase II intervention trial for cervical dysplasia
Population
Agent/dosage and schedule
Principal investigator
Duration, years
Study population
Prior colon adenoma
Piroxicam 7.5 mg/day
David S. AIberts, M.D. University of Arizona
9
100
Prior colon adenoma
Wheat Bran 13.5 g/day
David S. AIberts, M.D. University of Arizona
9
100
Prior colon adenoma
David S. AIberts, M.D. University of Arizona
9
25
Prior colon adenoma
DFMO 3, !.5, 0.75, 0.50, 0.25 Calcium carbonate 3 g/day
John A. Barton, M.D. Dartmouth College
5
637
Familial adenomatous polyposis
Sulindac 150 rag, 2 day for 9 months
Francis M. Giardiello, M.D. Johns Hopkins University
2
New Study
Prior colon adenoma
Vitamin E Vitamin C
Robert E. Greenberg, M.D. Dartmouth College
9
865
Prior colon adenoma
DFMO
Gordon D. Luk, M.D. Wayne State University
3
New Study
Prior colon
~-Carotene
Sohrab Mobarhan, M.D.
4
100 Planned
cancer
30 rag/day
Loyola Universityof Chicago
Prior colon adenoma
Calcium carbonate 3 |o 5 g/day
John D. Potter, M.D., Ph,D. University of Minnesota
3
New Study
Cervical dysplasia
~-Carotene 30 rag/day
Seymour L. Romney, M.D. Albert Einstein College of Medicine
4
New Study
Cervical dysplasia
[3.trans-Retinoic acid 0.372% tropical cervical cap
Earl A. Surwit, M.D. University of Arizona
7
301
Key concepts related to the development of cancer chemopreventlve agents
Long term of admin;,stration. Chemopreventive agents, which generally act either as antimutagens, as antiproliferafives, or as both, will have
~o be given to normal individuals over a period of years or even a lifetime.
Oral route of administration. Generally, a chemopreventive agent will be given by the oral route because it will be administered to normal individuals over a long period of time. Basic
295
investigators should therefore be aware that for a candidate chemopreventive agent to have potential, it will have to survive the digestive processes of the gastrointestinal tract.
Matching of toxic side effects to degree of cancer r/sk. In the event that a cancer chemopreventive agent is efficacious but is associated with significant side effects, the target population to consider will have to be one with higher cancer risk. For example, the severe oral and nasal irritation and drying associated with 13-c/s-retinoic acid, while objectionable to normal individuals, would be tolerated by persons who have had a carcinoma of the aerodigestive tract removed and carry a 10% chance of developing a second primary cancer of the esophagus, larynx, oral cavity, or lung. Conclusions
Twelve Phase I and 22 Phase II and III clinical trials sponsored by the Chemoprevention Branch are under way. The Phase II and III trials are testing the first generation of candidate chemopreventive agents, which are the retinoids, /3carotene, and calcium compounds. A second generation of six promising new compounds are in Phase I clinical trials. A problem of increasing concern is the time span of many years required to carry out a full clinical evaluation of a candidate chemopreventive agent. One important solution will be the development and validation of intermediate biomarkers of cancer, i.e., precancerous biological changes in target epithelia that are strongly associated with cancer risk and that can be modulated with a chemopreventive agent. Such intermediate markers could significantly shorten the clinical efficacy evaluation of promising agents in Phase II trials. Examples of such epithelial markers are abnormal histology (dysplasia), prevention or reversal of nuclear aberrations (micronuclei), ornithine decarboxylase a n d / o r prostaglandin
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